New treatment for seizures

Alison Barth, assistant professor of biological sciences at Carnegie Mellon University, received a $50,000 grant from the Milken Family Foundation to further her research on a novel treatment for seizures. A drug that acts on a single ion channel is the key to this new treatment, which she hopes will one day be used to prevent seizures in children.

Barth’s research identified a specific neuronal target that, when blocked with the drug, significantly reduced seizure occurrence and frequency in vitro. The real surprise came when she made the switch from in vitro to in vivo, testing the drug within a living organism and finding that it worked very well.

The target in question is an ion channel, a structure through which ions, or charged atoms, can cross cellular membranes. Ion flow in and out of nerve cells controls the chemical and electrical levels necessary for action potentials to occur. An action potential is an electrical signal — a messenger — that travels from neuron to neuron, relaying information as it goes.

Ion channels are directly responsible for electrical activity in a nerve cell, and malfunctions are a likely cause of seizures. Seizures occur when abnormal electrical activity in the brain results in involuntary changes in function or behavior. Barth looked at graphs of action potentials from neurons of healthy mice and mice that had had seizures. Action potentials have well documented and consistent shapes. A normal action potential would therefore look different than one recorded during a seizure.

“It’s a lot like Sesame Street,” Barth said. “They show you four [pictures] and say: ‘Which one doesn’t belong?’” In this way, Barth was able to identify which ion channel was responsible for the recorded changes in action potentials during a seizure.

Barth noted that the chances of having a seizure in a lifetime are very low, around one percent. However, one seizure increases the likelihood of a second 50-fold. The chances of having a third seizure increase by 80 to 90 percent, and the numbers continue to rise.

Spontaneous recurrent seizures, commonly known as epilepsy, affect between 1.4 and 2.7 million people in the U.S., according to the Centers for Disease Control and Prevention.

Barth hopes to interrupt the development of epilepsy from recurrent seizures. “I’m a newcomer to the epilepsy field,” Barth said. “The grant allows researchers with novel ideas and new approaches a chance to explore.”

To test its efficacy, Barth injected the drug into mice, though still unsure of the rate at which it would be metabolized or the likelihood that it would cross the blood-brain barrier to reach neurons. After several trials, Barth found that administering the drug concurrently with seizure induction effectively eliminated all seizures. “We stumbled upon this finding,” Barth said. “I just asked a student try the experiment.”

Barth pointed out that the core discovery was that “this particular target treatment could prevent seizures in vivo.” That is, the drug could be administered to a living animal and produce results.
“It is likely to be an orally administered drug, based upon the compound’s structure, although we haven’t tried it,” Barth said. “And it might be effective for people at risk of developing epilepsy and could be a therapy to prevent epileptogenesis.”

This is good news, particularly for young children, who make up a third of all newly diagnosed cases of epilepsy each year and are in danger of developing more severe forms of epilepsy as they grow older. The drug’s efficacy is another reason why Barth is eager to push her research forward so that it can go on to clinical trials.

“For a new drug to get to the clinic, it has to be commercially attractive,” Barth said. She is currently in the process of protecting the compound with a patent. However, there is still much work to be done before clinical trials start, including finding a company to partner with. “We would like to work with someone who will pursue this further,” Barth said.

The grant has given Barth a big imperative to make progress. “It is a one-year grant,” Barth said. “We received the money very quickly and therefore we can really do a lot of experiments to investigate this.”

Barth hopes her research advances will help her obtain a larger grant from the National Institutes of Health. She is also looking for other sources of funding. “It’s a clinically exciting compound,” Barth said, “and we are trying to get it to the clinic as soon as possible.”

The progression of this project was “a tribute to basic research and persistence,” Barth said. “It has spawned a dozen other projects in the lab.” Future research projects for her lab include examining the possibility of predicting if and when spontaneous recurrent seizures will develop. Those seizures could then be prevented with Barth’s innovative treatment.